It appears likely that the transducer mechanism responsible for excitation and prolonged sensitization of nociceptive afferent discharges is a chemically mediated process linked to injury of innervated tissue, called 'neurogenic inflammation.' This nerve-dependent aspect of the inflammatory process is believed to underlie cutaneous hyperalgesia and many of the conditions of chronic pain. A first step in understanding this process is to identify, characterize and determie the distribution and relationship of cutaneous nociceptive fibers and to distinguish those specialized biochemical features that might account for the specificity of inflammatory action on nociceptors. A series of experiments are planned to be performed on skin of laboratory rats with emphasis on the unmyelinated axons forming the majority of the sensory nerve population. Sensory axons will be identified by injecting axon-transported labels into dorsal root ganglion and, in some experiments, by comparing neurotoxins specific for thin sensory fibers (capsaicin) or unmyelinated sympathetic axons (6-hydroxydopamine). Specific markers will be employed to determine the distribution of sensory axons involved in tachykinin (e.g. substance P) mediated antidromic vasodilatation and plasma extravasation, their receptor binding sites (e.g. specific tritiated substance P binding), the binding sites of known endogenous algogenic substances (e.g. bradykinin), and the immunocytochemical detection of highly specific receptors for the Fc domain of IgG2b molecules on the surface of macrophages, the binding of which is believed to trigger release of arachidonic acid and synthesis of prostanoids. Co-localization studies with multiple labels should provide criteria for distinguishing the variety of unmyelinated sensory axon patterns and the correlates of efferent effects mediated by these axons of possible relevance in neurogenic inflammation. A variety of new methods are to be employed for multiple markers of transported proteins, neuropeptides, enzymes and antigenic sites specific to the small ganglion cells known to emit thin, primarily nociceptive, axons and to describe the unexplored fine structure of unmyelinated nociceptors. The findings should reveal the specificity of biochemical correlates with sense organ and efferent terminal patterns at the electron microscopic level and provide clues concerning the distribution of nociceptive axons in relation to other elements invoked in the inflammatory processes underlying prolonged pain.